X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death

THE Bcl-2 family of proteins regulate programmed cell death by an unknown mechanism 1 . Here we describe the crystal and solution structures of a Bcl-2 family member, Bcl-x L (ref. 2). The structures consist of two central, primarily hydrophobic α-helices, which are surrounded by amphipathic helices. A 60-residue loop connecting helices αl and α2 was found to be flexible and non-essential for anti-apoptotic activity. The three functionally important Bcl-2 homology regions (BH1, BH2 and BH3) 3–5 are in close spatial proximity and form an elongated hydrophobic cleft that may represent the binding site for other Bcl-2 family members. The arrangement of the α-helices in Bcl-x L is reminiscent of the membrane translocation domain of bacterial toxins, in particular diphtheria toxin and the colicins 6 . The structural similarity may provide a clue to the mechanism of action of the Bcl-2 family of proteins.